The Pulmonary-Allergy Drugs Advisory Committee, a group of outside medical advisers to the FDA, will meet Wednesday to vote on whether roflumilast is safe and effective enough for approval. The FDA does not have to follow the advice of its advisory panels, but it usually does.

Manufactured by the Forest Research Institute, the 500 mcg once-daily tablet acts as an anti-inflammatory agent in patients with COPD. There are currently no PDE4 inhibitors approved for use in the U.S.

Roflumilast has been in the FDA's regulatory pipeline for 15 years and includes 18 phase II or III clinical trials with varying endpoints.

FDA reviewers highlighted four trials in background material posted in advance of Wednesday's meeting -- two that showed roflumilast improved airflow and reduced moderate to severe exacerbations better than placebo, and two that showed it did not.

In two of the trials evaluating severe COPD -- dubbed M2-124 and M2-125 -- researchers recruited patients older than 40 who had severe airflow limitation, symptoms of chronic bronchitis, and a history of exacerbations. In the two trials, 1,537 patients were assigned to roflumilast (500 mcg/day taken orally) and 1,554 to placebo for one year.

Roflumilast bested placebo on both primary outcomes.

The drug resulted in a significantly greater change in prebronchodilator FEV1, improving it by 48 mL over the course of the study (P<0.0001).

In addition, roflumilast reduced the rate of moderate or severe exacerbations by 17% -- from 1.37% to 1.14% (P<0.003). The number needed to treat for the reduction of exacerbations was 5.29 in one of the studies and 3.64 in the other.

However, two other studies that tested the drug in a broader COPD population failed to demonstrate a significant difference in exacerbation rate between roflumilast and placebo.

The FDA researchers said the overall body of studies show only a "modest" difference in lung function between the two groups.

"While the difference in FEV1 between roflumilast and placebo was statistically significant in the clinical studies, the differences between the groups in mean change from baseline were quite modest at approximately 50 mL," concluded FDA researchers Anthony Durmowicz, MD, and Badrul Chowdhury, MD, PhD.

Patients taking roflumilast experienced a number of adverse events: altogether, 14% of the patients in the trial discontinued the drug because of problems that included weight loss, psychiatric events including suicide, and the potential for cancer. Diarrhea and nausea were the leading causes of discontinuation.

Psychiatric adverse events were more common in roflumilast patients than in patients taking placebo (6% versus 3%), and roflumilast patients reported a two- to threefold greater incidence of insomnia, anxiety, and depression-related adverse events compared with placebo.

"Of significant concern are the occurrence of three completed suicides and two suicide attempts in COPD patients compared to no suicides/suicide attempts in patients receiving placebo," FDA reviewers wrote.

Also of concern was the greater incidence of cancer. A total of 218 cancer/tumor events were reported in 208 patients -- 60% of whom were in the roflumilast group,and 40% of whom were in the placebo group.

In Forest's briefing documents prepared for the advisory panel meeting, the company says six key studies "consistently demonstrated efficacy of 500 mcg roflumilast over placebo in reducing the rate of moderate to severe exacerbations and improving lung function."

Several months ago, Forest Research narrowed the proposed indication for the drug.

The company originally sought approval of roflumilast for maintenance treatment of COPD. Now, it is seeking approval for reducing exacerbations of COPD associated with chronic bronchitis in patients at risk of exacerbations.

"This change of indication six months into the review period and two months prior to the advisory committee meeting is problematic because it shifts the focus of the efficacy analysis, which was based upon the original indication." the FDA reviewers said.

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